Rajendar K Mittapalli1, Patrick Marroum1, Yihong Qiu2, Kathleen Apfelbaum2, Hao Xiong3. 1. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA. 2. Drug products, Operations Science and Technology, AbbVie Inc., North Chicago, Illinois, USA. 3. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois, 60064, USA. hao.xiong@abbvie.com.
Abstract
PURPOSE: To develop and validate a Level A in vitro-in vivo correlation (IVIVC) for potassium chloride extended-release (ER) formulations. METHODS: Three prototype ER formulations of potassium chloride with different in vitro release rates were developed and their urinary pharmacokinetic profiles were evaluated in healthy subjects. A mathematical model between in vitro dissolution and in vivo urinary excretion, a surrogate for measuring in vivo absorption, was developed using time-scale and time-shift parameters. The IVIVC model was then validated based on internal and external predictability. RESULTS: With the established IVIVC model, there was a good correlation between the observed fraction of dose excreted in urine and the time-scaled and time-shifted fraction of the drug dissolved, and between the in vitro dissolution time and the in vivo urinary excretion time for the ER formulations. The percent prediction error (%PE) on cumulative urinary excretion over the 24 h interval (Ae0-24h) and maximum urinary excretion rate (Rmax) was less than 15% for the individual formulations and less than 10% for the average of the two formulations used to develop the model. Further, the %PE values using external predictability were below 10%. CONCLUSIONS: A novel Level A IVIVC was successfully developed and validated for the new potassium chloride ER formulations using urinary pharmacokinetic data. This successful IVIVC may facilitate future development or manufacturing changes to the potassium chloride ER formulation.
RCT Entities:
PURPOSE: To develop and validate a Level A in vitro-in vivo correlation (IVIVC) for potassium chloride extended-release (ER) formulations. METHODS: Three prototype ER formulations of potassium chloride with different in vitro release rates were developed and their urinary pharmacokinetic profiles were evaluated in healthy subjects. A mathematical model between in vitro dissolution and in vivo urinary excretion, a surrogate for measuring in vivo absorption, was developed using time-scale and time-shift parameters. The IVIVC model was then validated based on internal and external predictability. RESULTS: With the established IVIVC model, there was a good correlation between the observed fraction of dose excreted in urine and the time-scaled and time-shifted fraction of the drug dissolved, and between the in vitro dissolution time and the in vivo urinary excretion time for the ER formulations. The percent prediction error (%PE) on cumulative urinary excretion over the 24 h interval (Ae0-24h) and maximum urinary excretion rate (Rmax) was less than 15% for the individual formulations and less than 10% for the average of the two formulations used to develop the model. Further, the %PE values using external predictability were below 10%. CONCLUSIONS: A novel Level A IVIVC was successfully developed and validated for the new potassium chloride ER formulations using urinary pharmacokinetic data. This successful IVIVC may facilitate future development or manufacturing changes to the potassium chloride ER formulation.
Entities:
Keywords:
dissolution; extended-release formulation; in vitro/in vivo correlations (IVIVC); level A correlation; pharmacokinetics; potassium chloride; prediction error; urinary excretion data
Authors: H Malinowski; P Marroum; V R Uppoor; W Gillespie; H Y Ahn; P Lockwood; J Henderson; R Baweja; M Hossain; N Fleischer; L Tillman; A Hussain; V Shah; A Dorantes; R Zhu; H Sun; K Kumi; S Machado; V Tammara; T E Ong-Chen; H Mahayni; L Lesko; R Williams Journal: Adv Exp Med Biol Date: 1997 Impact factor: 2.622